PROJECT SUMMARY/ABSTRACT The most common primary intracranial tumors, meningiomas1,2, also happen to be most commonly benign?and therein lies the problem. Because of their perceived benignity, they have been relatively unstudied despite the fact that some are indeed malignant and the intracranial location of even benign meningiomas can be lethal. Unfortunately, meningiomas are resistant to radiation and chemotherapy4, leaving surgery as the primary treatment, but grade II (atypical) and III (malignant) tumors invariably recur, requiring multiple operations accompanied by increasing morbidity until the tumors become inoperable. Yet, despite their prevalence and terrible morbidity, our understanding of their etiology remains rudimentary. We know that certain risk factors, such as mutations in the neurofibromatosis gene (NF2), female sex (the tumors bear hormone receptors), and exposure to ionizing radiation, markedly increase their incidence5, and the greatly increased risk of meningioma in a number of cancer syndromes suggests a genetic basis. Targeted next- generation sequencing studies have identified some genetic pathways involved in the development of benign meningiomas,6-8 but these studies have been small and frequently do not distinguish between tumors of different grades. It is not clear, in fact, whether the three grades of tumors reflect a single disease process or whether high-grade tumors are actually a different disease entity from the outset, but I hypothesize that high- grade meningiomas bear specific somatic mutations that make them malignant. My goal is to understand the mechanisms that cause meningioma to undergo malignant transformation and to develop potential biomarkers and therapeutic targets. My preliminary data, based on whole exome sequencing (WES), RNA sequencing (RNA-seq), and single nucleotide polymorphism (SNP) array studies of 14 high-grade and 16 benign meningioma samples, support our hypothesis but need to be expanded. Nevertheless, we have already identified a compelling candidate in ARID1A, which encodes a core component of the Switch/Sucrose Non- Fermentable (SWI/SNF) nucleosome remodeling complex that has been found to act as a tumor suppressor in various malignancies9-14. Located on chromosome 1p, whose deletion has been long associated with high-grade meningiomas, ARID1A could provide a molecular mechanism for progression15-18. I therefore propose to examine our collection of over 100 patient samples?the largest collection of meningioma samples to date?to identify the molecular signatures of low-grade and high-grade meningiomas (Aim 1). In Aim 2, I will determine the role of ARID1A in malignant progression of meningiomas. The proposed research would vastly increase our understanding of the molecular genetics of high-grade meningiomas, allow for early identification of cases that will behave poorly, and lay the groundwork for potential targeted therapies for this devastating affliction.